Chloroalkyl pyridinium hydrochloride compounds, and chloromethyl pyridinium hydrochloride compounds, also called picolyl chloride hydrochloride compounds, are generally used in the preparation of various pharmaceuticals, dyes, agricultural products and particularly as pharmaceutical intermediates. As such, chloroalkyl pyridinium hydrochloride compounds having significant impurity levels are very undesirable and oftentimes not tolerated in the end product for which it is used. It is therefore advantageous to use chloroalkyl pyridinium hydrochloride compound in its most pure form.
In addition to purity, it is also beneficial if the morphology of the chloroalkyl pyridinium hydrochloride compound is one which is easy to handle from a processability standpoint. Current chloroalkyl pyridinium hydrochloride compounds, particularly 3-chloromethyl pyridinium hydrochloride, are available as solid powders that tend to clump and/or create dust problems and difficult to contain. For those reasons they can pose processing, safety and/or environmental problems, particularly since some chloroalkyl pyridinium hydrochloride compounds ere reported to be carcinogenic.
Despite the desire for relatively pure chloroalkyl pyridinium hydrochloride compounds that facilitate efficient processibility, the known methods for producing chloroalkyl pyridinium hydrochloride compounds, and particularly chloromethyl pyridinium hydrochloride, fail to provide such compounds.
In Mosher, Harry S. et al., Journal Of American Chemical Society, 73 Oct.(1951) pp.4925-4927, 3-chloromethyl and 4-chloromethyl pyridinium hydrochloride was prepared by first reducing ethyl nicotinate and ethyl isonicotinate with lithium aluminum hydride in anhydrous ether to produce 3-hydroxymethyl pyridine and 4-hydroxymethyl pyridine respectively. The resulting liquid 3-hydroxymethyl pyridine was separated from the distillate by converting to the hydrochloride. The 3- and 4-hydroxymethyl pyridine hydrochloride were added to a substantial excess amount of thionyl chloride and then refluxed followed by the addition of benzene to precipitate out the 3- and 4-chloromethyl pyridine hydrochloride, respectively. Although the resulting 3-chloromethyl pyridine hydrochloride compound appears to be very pure, it apparently exists as a fluffy dusty powder which is difficult to process on a large scale basis.
Vejdelek, Zdenek J. et al. in Collection Czechoslov. Chem. Communs. 16, (1951) pp.344-7, discloses the preparation of 3-chloromethyl pyridinium hydrochloride from 3-hydroxymethyl pyridine and thionyl chloride in chloroform.
Japanese patent no. 3-271290 discloses the chlorination of 2-[4-(3-hydroxymethyl-2-pyridyl)oxyphenyl]propionic acid by thionyl chloride in benzene to give 2-[4-[3-(chloromethyl)-2-pyridyl]oxyphenyl]propionic acid.
Acosta, C. Kirk et al. J. Chem. Res., Synop. (5), (1991) pp. 110-11 discloses processes for synthesizing various unnatural amino acids. In the disclosed method of synthesis, 3-hydroxymethylquinoline is reacted with hydrogen chloride and thionyl chloride to produce reportedly good yields of 3-chloroalkylquinoline. No solvent is used and there is no description as to reactant amounts and the purity of the resulting 3-chloroalkylquinoline.
In Org. Prep. Proced. Int. 24 (2) (1992)pp.143-146, 5-bromo-3-hydroxymethylpyridine was reacted with hydrogen chloride in diethyl ether. The resulting precipitate was collected by vacuum filtration and then dissolved in thionyl chloride and refluxed. Diethyl ether was used to precipite the 5-bromo-3-chloromethylpyridinium hydrochloride product. Since the product produced was reportedly off white in color this method apparently does not provide a highly pure product.
While it is known to use thionyl chloride to produce chloroalkyl pyridinium hydrochloride, it appears that the known procedures either generate high levels of impurities and/or produce a solid product that has handling problems, e.g., dusting, clumping. Moreover, many of the known procedures produce low yields or are very difficult to perform on a large scale. In view of these shortcomings, there exists a need for an improved process for producing chloroalkyl pyridinium hydrochloride compounds and especially a process for preparing very pure chloroalkyl pyridinium hydrochloride compounds in a form that is easy to process.
The inventors of the instant invention have surprisingly discovered a process for preparing highly pure, i.e., at least about 97 weight percent pure, chloroalkyl pyridinium hydrochloride compounds, including analogs and regioisomers thereof, in a substantially non-dusting, free-flowing form which has processing advantages.
In the processes of the instant invention, thionyl chloride is admixed with a solution or dispersion of a hydroxyalkyl pyridinium hydrochloride compound in a liquid component which is a non-solvent for the chloroalkyl pyridinium hydrochloride product. Preferably, the solution or dispersion of hydroxyalkyl pyridinium hydrochloride is prepared by reacting a minimum amount of hydrogen chloride or hydrochloric acid with a hydroxyalkyl pyridine compound in a liquid hydrocarbon, preferably an aromatic hydrocarbon such as toluene. The hydroxyalkyl pyridinium hydrochloride in the solution or dispersion reacts with thionyl chloride to form the chloroalkyl pyridinium hydrochloride, a portion of which spontaneously forms as a solid or crystallizes in the reaction mixture. Highly pure, dust-free, free-flowing powders of chloroalkyl pyridinium hydrochloride, including 3-chloromethyl pyridinium hydrochloride, can be recovered from the reaction mixture in high yields on the order of at least about 97 percent, based on the molar equivalents of hydroxyalkyl heterocyclic aromatic compounds (usually the equivalents of hydroxyalkyl pyridine), preferably at least about 99 percent, same basis.